Acute uncomplicated urinary tract infections (UTIs) occur in an estimated 7-11 million women each year, and the annual costs of caring for these women are thought to approach $1.6 billion. Approximately 20-30% of women suffer from frequent recurrent infections. UTIs in young women result in substantial morbidity, time lost from work, and medical costs. An improved understanding of the pathogenic mechanisms underlying UTIs could result in novel approaches to their prevention and reduced morbidity and antimicrobial use. In this project we seek a better understanding of the pathogenesis of UTI. The widely accepted model of UTI pathogenesis is that vaginal colonization with uropathogens from the rectal flora precedes urethral and bladder colonization and subsequent UTI, but the temporal relationship between these events has not been established and some women with UTI cannot be found to harbor vaginal uropathogens. Moreover, recent data from studies in mice strongly suggest that persistent bladder epithelial infection follows an initial bladder infection. In this project, we will prospectively follow a large cohort of women with recurrent UTI to determine 1) the temporal relationships between vaginal colonization with a uropathogen, asymptomatic bacteriuria and symptomatic UTI and 2) the presence of persistent bladder epithelial infection following symptomatic UTI and its relationship to same-strain recurrence of UTI. We will thus be able to determine the relative importance of vaginal colonization vs. persistent infection of the bladder epithelium as the origin of the infecting strain in same-strain recurrent UTI. Uropathogenic strains isolated from well-characterized episodes of UTI and asymptomatic bacteriuria will undergo genotyping in Project 1 to identify unique genes or gene dusters that may contribute to their clinical phenotype. The molecular pathogenesis of representative strains will also be examined in Project 1 and their effect on host response will be determined by functional genomic analysis in Project 3. A better understanding of the molecular and epidemiologic basis of UTI is critical in developing optimal prevention and management strategies.